4-(benzylidene-amino)-3-(methylsulfanyl)-4h-(1,2,4)triazin-5-one derivatives having a PDE-IV inhibiting and TNF-antagonistic effect for the treatment of cardiac diseases and allergies

ABSTRACT

Triazine derivatives of the formula (I) and physiologically acceptable salts and solvates thereof, in which R 1 , R 2 , A and R 5  are as defined in Claim  1 , exhibit phosphodiesterase IV inhibition and can be employed for the treatment of allergic diseases, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory diseases, autoimmune diseases, such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn&#39;s disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disorders, atherosclerosis and AIDS, furthermore for inhibiting the formation of TNFα.

The invention relates to compounds of the formula I

in which

-   R¹ and R² are each, independently of one another, H, OH, OR⁶, SR⁶,    SOR⁶, SO₂R⁶, Hal or together are alternatively —O—CH₂—O—,-   A is R³- and R⁴-substituted phenyl, 2-, 3- or 4-pyridyl, 4- or    5-pyrimidyl, 3- or 4-pyridazyl or 2- or 3-pyrazinyl,-   R³ and R⁴ are each, independently of one another, H, OH, OR⁶, SR⁶,    SOR⁶, SO₂R⁶, R⁶, Hal or together are alternatively —O—CH₂—O—,-   R⁵ is H or alkyl having from 1 to 10 carbon atoms,-   R⁶ is alkyl having from 1 to 10 carbon atoms, which may be    substituted by from 1 to 5 F and/or Cl atoms, cycloalkyl having 3-7    carbon atoms, alkylenecycloalkyl having 5-10 carbon atoms or alkenyl    having 2-8 carbon atoms,-   Hal is F, Cl, Br or I,    and physiologically acceptable salts and solvates thereof.

Similar compounds are already known (for example CAS Reg. No.292057-55-7). However, the compounds according to the invention differfrom the known compounds in the nature and position of the substituents.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been found that the compounds of the formula I and salts andsolvates thereof have very valuable pharmacological properties and arewell tolerated.

In particular, they exhibit selective phosphodiesterase IV inhibitioncombined with an intracellular increase in cAMP (N. Sommer et al.,Nature Medicine, 1, 244-248 (1995)).

The PDE IV inhibition can be demonstrated, for example, analogously toC. W. Davis in Biochim. biophys. Acta 797, 354-362 (1984).

The compounds according to the invention can be employed for thetreatment of asthmatic diseases. The antiasthmatic action of PDE IVinhibitors has been described, for example, by T. J. Torphy et al. inThorax, 46, 512-523 (1991) and can be determined, for example, by themethod of T. Olsson, Acta allergologica 26, 438-447 (1971).

Since cAMP inhibits bone-degrading cells and stimulates bone-formingcells (S. Kasugai et al., M 681 and K. Miyamoto, M 682, in Abstracts ofthe American Society for Bone and Mineral Research 18^(th) AnnualMeeting, 1996), the compounds according to the invention can be employedfor the treatment of osteoporosis.

The invention therefore furthermore relates to the use of the compoundsof the formula I and/or physiologically acceptable salts and solvatesthereof for the preparation of a medicament for the treatment andprophylaxis of diseases which are caused by an excessively low cAMPlevel and/or can be influenced by an increase in the cAMP level.

In addition, the compounds exhibit an antagonistic action to theproduction of TNFα (tumour necrosis factor) and are therefore suitablefor the treatment of allergic and inflammatory diseases, autoimmunediseases, such as, for example, rheumatoid arthritis, multiplesclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis,transplant rejection reactions, cachexia and sepsis.

The antiinflammatory action of the substances according to the inventionand the efficacy thereof for the treatment of, for example, autoimmunediseases, such as multiple sclerosis or rheumatoid arthritis, can bedetermined analogously to the methods of N. Sommer et al., NatureMedicine 1, 244-248 (1995) or L. Sekut et al., Clin. Exp. Immunol. 100,126-132 (1995).

The compounds can be employed for the treatment of cachexia. Theanticachectic action can be tested in TNF-dependent models of cachexia(P. Costelli et al., J. Clin. Invest. 95, 2367ff. (1995); J. M. Argileset al., Med. Res. Rev. 17, 477ff. (1997)).

PDE IV inhibitors can also inhibit the growth of tumour cells and aretherefore suitable for tumour therapy (D. Marko et al., Cell Biochem.Biophys. 28, 75ff. (1998)). The action of PDE IV inhibitors in thetreatment of tumours is described, for example, in WO 95 35 281, WO 9517 399 or WO 96 00 215.

The invention therefore furthermore relates to the use of the compoundsof the formula I and/or physiologically acceptable salts and solvatesthereof for the preparation of a medicament for the treatment andprophylaxis of diseases which are caused by excessive production oftumour necrosis factor (TNF) and/or can be influenced by a reduction inthe production of TNF.

PDE IV inhibitors can prevent mortality in models for sepsis and aretherefore suitable for the therapy of sepsis (W. Fischer et al.,Biochem. Pharmacol. 45, 2399ff. (1993)).

They can furthermore be employed for the treatment of memory disorders,atherosclerosis, atopic dermatitis and AIDS.

The action of PDE IV inhibitors in the treatment of asthma, inflammatorydiseases, diabetes mellitus, atopic dermatitis, psoriasis, AIDS,cachexia, tumour growth or tumour metastases is described, for example,in EP 779291.

The compounds of the formula I have broad potential therapeuticapplications as inhibitors of PDE IV isozymes since the PDE IV family ofisozymes plays a crucial role in the physiology of all mammals. PDE IVisozymes effect intracellular hydrolysis of adenosine3′,5′-monophosphates (cAMP) in pro-inflammatory leukocytes. cAMP is inturn responsible for mediation of the action of numerous hormones in thebody.

There is a vast literature which describes the effects of PDE inhibitorson a wide variety of inflammatory cell responses, which, in addition toincreasing the cAMP level, also include inhibition of superoxideproduction, degranulation, chemotaxis and liberation of tumour necrosisfactor (TNF) in eosinophiles, neutrophiles and monocytes.

The invention therefore furthermore relates to the use of the compoundsof the formula I and/or physiologically tolerated salts and/or solvatesthereof for the preparation of a medicament for the treatment orprophylaxis of diseases which are caused by disorders in the regulationof the activation and degranulation of human eosinophiles.

The compounds of the formula I can be employed as medicament activeingredients in human and veterinary medicine. They can furthermore beemployed as intermediates for the preparation of further medicamentactive ingredients.

The compounds of the formula I can preferably also be used together withone or more known PDE IV inhibitors. The compounds of the formula I arepreferably used together with one or more of the PDE IV inhibitorspublished in the following documents: EP 0763534, WO 99/65880, WO99/08047, WO 98/06704, WO 00/59890, DE 19604388, DE 19932315, EP0723962, EP 0738715.

The invention also relates to the use of the compounds of the formula Ias PDE IV inhibitors for the treatment of myocardial diseases.

Coronary heart disease is the most frequent cause of death in westerncountries. If a coronary artery is critically narrowed, the reducedblood flow can result in myocardial ischaemia. Depending on the severityof the prior ischaemic period, commencement of reperfusion results inreversible or irreversible myocardial damage which is characterised bylong-lasting depression or an irreversible loss of contractile function.Depending on the size of the affected myocardial area, acute or chronicheart failure can occur.

A particular clinical problem in the above-described scenario is theonset of restenosis after an initially successful reperfusionintervention by PTCA (percutaneous transluminal coronary angioplasty),even after stent implantation, thrombolysis or the insertion of anaorto-coronary bypass. Animal experiment and clinical studies indicatethat inflammatory processes play a causative role in the variousabove-mentioned heart diseases, for example in coronary heart diseaseitself, in reversible or irreversible myocardial ischaemia/reperfusiondamage, in acute or chronic heart failure and in restenosis, includingin-stent restenosis and stent-in-stent restenosis. Resident and invadingmacrophages as well as neutrophilic cells and TH1 and TH2 helper cellsare involved in these inflammatory processes. This leukocyte reactionresults in a characteristic cytokine pattern involving TNF-α, IL-1β,IL-2 and IL-6 as well as IL-10 and IL-13 (Pulkki K J: Cytokines andcardiomyocyte death, Ann. Med. 1997 29: 339-343. Birks E J, Yacoub M H:The role of nitric oxide and cytokines in heart failure. Coron. Artery.Dis. 1997 8: 389-402).

It has been found that these species are formed in human patients withmyocardial ischaemia. Animal models show that cytokine productioncorrelates with invasion by peripheral macrophages and neutrophiliccells, which can spread the damage into the still intact myocardium.However, the main role in the cytokine reaction is played by TNF-α,which integrates inflammatory and pro-apoptotic reactions and inaddition has a direct negative ionotropic effect on myocardial cells(Ceconi C, Curello S, Bachetti T, Corti A, Ferrari R: Tumor necrosisfactor in congestive heart failure: a mechanism of disease for the newmillennium? Pro. Cardiovas. Dis. 1998 41: 25-30. Mann D L: The effect oftumor necrosis factor-alpha on cardiac structure and function: a tale oftwo cytokines. J. Card. Fail. 1996 2: S165-S175. Squadrito F, AltavillaD, Zingarelli B, et al.: Tumor necrosis factor involvement in myocardialischaemia-reperfusion injury. Eur. J. Pharmacol. 1993 237: 223-230).

Animal models of cardiac infarction have shown that rapid release ofTNFα occurs during the reperfusion phase (Herskowitz A, Choi S, Ansari AA, Wesselingh S: Cytokine mRNA expression in postischemic/reperfusedmyocardium. Am. J. Pathol. 1995 146: 419-428) and that the protectiveaction of medicaments, such as dexamethason (Arras M, Strasser R, MohriM, et al.: Tumor necrosis factor-alpha is expressed bymonocytes/macrophages following cardiac microembolization and isantagonized by cyclosporine, Basic. Res. Cardiol. 1998 93:97-107),cyclosporin A (Arras M, Strasser R, Mohri M, et al.: Tumor necrosisfactor-alpha is expressed by monocytes/macrophages following cardiacmicroembolization and is antagonized by cyclosporine, Basic. Res.Cardiol. 1998 93:97-107, Squadrito F, Altavilla D, Squadrito G, et al.:Cyclosporin-A reduces leukocyte accumulation and protects againstmyocardial ischaemia reperfusion injury in rats. Eur. J. Pharmacol. 1999364: 159-168) or clorichromene (Squadrito F, Altavilla D, Zingarelli B,et al.: The effect of cloricromene, a coumarine derivative, on leukocyteaccumulation, myocardial necrosis and TNF-alpha production in myocardialischaemia-reperfusion injury. Life Sci. 1993 53: 341-355), is associatedwith a reduction in the TNF-α in circulation.

The present invention therefore also relates to the use of the compoundsof the formula I and/or physiologically acceptable salts and solvatesthereof for the preparation of a medicament for the treatment andprophylaxis of diseases which can be influenced by a reduction in theproduction of tumour necrosis factor (TNF).

The PDE IV inhibitors of the formula I are potential antagonists of theproduction of macrophages and T-cell cytokines. In addition, theyinhibit the proliferation of T-cells. As a consequence, PDE IVinhibition can have an advantageous effect in myocardial diseases inwhich there is a causal link to the production of cytokines andinflammatory processes.

The use of the compounds of the formula I and/or physiologicallyacceptable salts and solvates thereof for the preparation of amedicament for the treatment and prophylaxis of diseases which is causedby excessive production of macrophages and T-cells and/or can beinfluenced by a reduction in macrophage and T-cell production islikewise a subject-matter of the present invention.

The present invention furthermore relates to the use of the compounds ofthe formula I and/or physiologically acceptable salts and solvatesthereof for the preparation of a medicament for the treatment andprophylaxis of diseases which are caused by excessive proliferation ofT-cells and/or can be influenced by inhibition of the proliferation ofT-cells.

Compared with PDE III inhibitors and the early PDE IV inhibitorrolipram, preferred PDE IV inhibitors of the formula I do not exhibitany haemodynamic side effects which could have a dose-limiting effect inthe treatment of most cardiovascular diseases.

The invention has the object of finding novel uses for compounds havingvaluable properties, in particular those which are suitable for thepreparation of medicaments.

It has been found that the PDE IV inhibitors of the formula I and saltsand solvates thereof exhibit very valuable pharmacological properties inthe treatment of myocardial diseases and at the same time are welltolerated.

The preferred compounds effect selective inhibition of phosphodiesteraseIV, which is associated with an intracellular increase in the cAMPconcentration (N. Sommer et al., Nature Medicine, 1, 244-248 (1995)).Inhibition of PDE IV can be demonstrated, for example, as described byC. W. Davis, Biochim. Biophys. Acta 797, 354-362 (1984).

The affinity of the compounds according to the invention forphosphodiesterase IV is measured by determining their IC₅₀ values (theinhibitor concentration necessary to inhibit the enzyme activity by50%).

The present application therefore furthermore relates to the use of thecompounds of the formula and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for the treatmentand prophylaxis of diseases which can be influenced by an increase inthe cAMP level.

The invention preferably provides the use of the above-mentionedcompounds for the preparation of a medicament for the treatment ofmyocardial diseases which have inflammatory and immunologicalcharacteristics.

The invention very particularly preferably provides the use of theabovementioned compounds for the preparation of a medicament for thetreatment of coronary heart disease, reversible or irreversiblemyocardial ischaemia/reperfusion damage, acute or chronic heart failure,decompensated cardiac insufficiency (congestive heart failure, CHF) andrestenosis, including in-stent restenosis and stent-in-stent restenosis.

The compounds of the formula and/or salts and/or solvates thereof arefurthermore suitable for the preparation of a medicament for theprophylaxis and treatment of ventricular remodelling after infarction ordecompensated cardiac insufficiency (congestive heart failure, CHF) ofvarying severity.

The preparations for the treatment of the diseases mentioned can beemployed as medicaments in human and veterinary medicine. Possibleexcipients are organic or inorganic substances which are suitable forenteral (for example oral) or parenteral administration or topicalapplication and which do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatine, carbohydrates, such as lactoseor starch, magnesium stearate, talc and Vaseline. In particular,tablets, pills, coated tablets, capsules, powders, granules, syrups,juices or drops are employed for oral administration, suppositories forrectal administration, solutions, preferably oil-based or aqueoussolutions, and furthermore suspensions, emulsions or implants forparenteral administration, and ointments, creams or powders for topicalapplication. It is also possible to lyophilise the novel compounds andto use the resultant lyophilisates, for example, for the preparation ofinjection preparations. The preparations indicated may be sterilisedand/or comprise adjuvants, such as, for example, lubricants,preservatives, stabilisers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, buffers, dyes, flavours and/or one ormore further active ingredients, for example one or more vitamins.

In these indications, the substances are generally preferablyadministered in doses of from about 1 to 500 mg, in particular from 5 to100 mg, per dosage unit. The daily dose is preferably from about 0.02 to10 mg/kg of body weight. However, the specific dose for the particularpatient depends on a number of factors, for example on the efficacy ofthe compound used, on the age, body weight, general state of health,sex, on the diet, on the time and method of administration, on theexcretion rate, the medicament combination and the severity of thedisease against which the therapy is employed. Oral administration ispreferred.

The invention accordingly relates to the compounds of the formula I andto a process for the preparation of compounds of the formula I accordingto claim 1 and salts and solvates thereof, characterised in that acompound of the formula II

in which

-   R¹ and R² are as defined,-   is reacted with a compound of the formula III

in which

-   A and R⁵ are as defined above,    and/or in that a basic compound of the formula I is converted into    one of its salts by treatment with an acid.

The novel compounds of the formula III are likewise a subject-matter ofthe invention.

The term “solvates of the compounds of the formula I” is taken to meanadductions of preferably inert solvent molecules onto the compounds ofthe formula I which form owing to their mutual attractive force.Solvates are, for example, monohydrates or dihydrates or alcoholates.

Above and below, the radicals R¹, R², A, R³, R⁴, R⁵ and R⁶ are asdefined under the formulae I, II and III, unless expressly statedotherwise.

R⁶ is preferably alkyl, furthermore preferably alkyl which issubstituted by from 1 to 5 fluorine and/or chlorine atoms, furthermorepreferably cycloalkyl.

In the above formulae, alkyl is preferably unbranched and has 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4, 5 or 6carbon atoms, and is preferably methyl, ethyl, trifluoromethyl,pentafluoroethyl or propyl, furthermore preferably isopropyl, butyl,isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl,isopentyl or n-hexyl. Particular preference is given to methyl, ethyl,trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl.

Cycloalkyl preferably has 3-7 carbon atoms and is preferably cyclopropyland cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl,furthermore also cycloheptyl, particularly preferably cyclopentyl.

Alkenyl is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl,furthermore preferably 4-pentenyl, isopentenyl or 5-hexenyl.

Alkylene is preferably unbranched and is preferably methylene orethylene, furthermore preferably propylene or butylene.

Alkylenecycloalkyl preferably has 5-10 carbon atoms and is preferablymethylenecyclopropyl, methylenecyclobutyl, furthermore preferablymethylenecyclopentyl, methylenecyclohexyl or methylenecycloheptyl,furthermore alternatively ethylenecyclopropyl, ethylenecyclobutyl,ethylenecyclopentyl, ethylenecyclohexyl or ethylenecycloheptyl,propylenecyclopentyl, propylenecyclohexyl, butylenecyclopentyl orbutylenecyclohexyl.

Hal is preferably F, Cl or Br, but alternatively I.

The radicals R¹ and R² may be identical or different. R² is preferablyin the 3-position of the phenyl ring. The radicals R¹ and R² are,independently of one another, for example, hydroxyl, —S—CH₃, —SO—CH₃,—SO₂CH₃, F, Cl, Br or I or together are methylenedioxy. However, theyare preferably each methoxy, ethoxy, propoxy, cyclopentoxy, but alsofluoro-, difluoro- or trifluoromethoxy or 1-fluoro-, 2-fluoro-,1,2-difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or 2,2,2-trifluoroethoxy.

R¹ is particularly preferably methoxy, ethoxy, cyclopentoxy orisopropoxy.

R² is particularly preferably methoxy or ethoxy.

A is preferably phenyl, 2-, 3- or 4-pyridyl, or 4- or 5-pyrimidyl,particularly preferably phenyl or 2-, 3- or 4-pyridyl, in particularphenyl or 3-pyridyl.

R³ and R⁴ are preferably in the ortho- and para-position to the —CH₂S—group on ring A. The radicals R³ and R⁴, in the case where A is aheteroaromatic ring, are also always bonded to a carbon atom in thering. R³ and R⁴ are in this case particularly preferably each an H atom.

R³ and R⁴, independently of one another, preferably adopt the meaning ofR⁶ or one of the meanings mentioned for R¹ and R². R³ is particularlypreferably methoxy, ethoxy, propoxy, cyclopentoxy, or alternativelyfluoro-, difluoro- or trifluoromethoxy or 1-fluoro-, 2-fluoro-,1,2-difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or 2,2,2-trifluoroethoxy.R⁴ is particularly preferably alkoxy or alkyl, in particular methoxy,ethoxy, propoxy, cyclopentoxy or methyl, ethyl, trifluoromethyl, propyl,isopropyl, butyl, n-pentyl, n-hexyl or n-decyl.

R⁵ is preferably in each case, independently of one another, H ormethyl, in particular methyl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to If, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ and R² are each, independently of one another, OR⁶;-   in Ib R¹ and R² are each, independently of one another, OR⁶,    -   R⁶ is alkyl having 1-10 carbon atoms or cycloalkyl having 3-7        carbon atoms;-   in Ic R¹ and R² are each, independently of one another, OR⁶,    -   R⁶ is alkyl having 1-10 carbon atoms or cycloalkyl having 3-7        carbon atoms,    -   A is phenyl, 2-, 3- or 4-pyridyl or 4- or 5-pyrimidyl,    -   R³ and R⁴ are each, independently of one another, R⁶, H, Cl, CF₃        or OR⁶;-   in Id R¹ and R² are each, independently of one another, OR⁶,    -   R⁶ is alkyl having 1-10 carbon atoms or cycloalkyl having 3-7        carbon atoms,    -   A is phenyl, 2-, 3- or 4-pyridyl or 4- or 5-pyrimidyl,    -   R³ and R⁴ are each, independently of one another, H, Cl, F, CF₃        or OR⁶,    -   R⁵ is H or methyl;-   in Ie R¹ and R² are each, independently of one another, OR⁶,    -   R⁶ is alkyl having 1-10 carbon atoms or cycloalkyl having 3-7        carbon atoms,    -   A is phenyl, 2-, 3- or 4-pyridyl or 4- or 5-pyrimidyl,    -   R³ and R⁴ are each, independently of one another, H, Cl, F, CF₃        or OR⁶,    -   R⁵ is methyl.

The compounds of the formula I and also the starting materials for thepreparation thereof are, in addition, prepared by methods known per se,as described in the literature (for example in the standard works, suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the formula I.

On the other hand, it is possible to carry out the reaction stepwise.

The compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

Some of the starting materials of the formulae II and III are known (forexample U.S. Pat. No. 3,905,801). If they are not known, they can beprepared by methods known per se.

In detail, the reaction of the compounds of the formula II with thecompounds of the formula III is carried out in the presence or absenceof a preferably inert solvent at temperatures between about −20 andabout 150°, preferably between 20 and 100°.

Examples of suitable solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether orethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethaneor nitrobenzene; esters, such as ethyl acetate, or mixtures of the saidsolvents.

In the reaction of compounds of the formula II with compounds of theformula III, it is possible to employ dehydrating agents, as are knownfor similar reactions of carbonyl compounds with amino compounds, inorder to shift the reaction equilibrium to the side of the products. Forexample, it is possible to use silica gel, molecular sieve, hygroscopicsalts, solvents or acids. Water formed during the reaction can likewisebe removed from the reaction mixture by conventional methods, such asevaporation or by means of a water separator. The equilibrium canfurthermore likewise be shifted by using a solvent in which the startingcompounds II and III are dissolved, but the compounds of the formula Iare not, so that product formed is removed from the equilibrium.

The pH necessary for the reaction can be set in accordance with pHvalues selected for similar reactions of carbonyl compounds with aminocompounds. A suitable added acid is preferably a carboxylic acid, inparticular acetic acid.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in a preferably inert solvent, such asethanol, followed by evaporation. Suitable acids for this reaction are,in particular, those which give physiologically acceptable salts. Thus,it is possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, orlaurylsulfuric acid. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

On the other hand, if desired, the free bases of the formula I can beliberated from their salts using bases (for example sodium hydroxide,potassium hydroxide, sodium carbonate or potassium carbonate).

The invention relates to compounds of the formula I and physiologicallyacceptable salts and solvates thereof as medicaments.

The invention also relates to the compounds of the formula I andphysiologically acceptable salts and solvates thereof asphosphodiesterase IV inhibitors.

The invention furthermore relates to the use of the compounds of theformula I and/or physiologically acceptable salts and/or solvatesthereof for the preparation of pharmaceutical preparations, inparticular by non-chemical methods. In this case, they can be convertedinto a suitable dosage form together with at least one solid, liquidand/or semi-liquid excipient or adjuvant and, if desired, in combinationwith one or more further active ingredients.

The invention furthermore relates to pharmaceutical preparationscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts and/or solvates.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatine, carbohydrates, such as lactoseor starch, magnesium stearate, talc or Vaseline. Suitable for oraladministration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders. The novel compounds mayalso be lyophilised and the resultant lyophilisates used, for example,for the preparation of injection preparations. The preparationsindicated may be sterilised and/or comprise adjuvants, such aslubricants, preservatives, stabilisers and/or wetting agents,emulsifiers, salts for modifying the osmotic pressure, buffersubstances, dyes and flavours and/or one or more further activeingredients, for example one or more vitamins.

The compounds of the formula I and physiologically acceptable salts andsolvates thereof can be employed for combating diseases, with anincrease in the cAMP (cycloadenosine monophosphate) level beingachieved, resulting in inhibition or prevention of inflammation andmuscle relaxation. In particular, the PDE IV inhibitors according to theinvention can be used in the treatment of allergic diseases, asthma,chronic bronchitis, atopic dermatitis, psoriasis and other skindiseases, inflammatory diseases, autoimmune diseases, such as, forexample, rheumatoid arthritis, multiple sclerosis, Crohn's disease,diabetes mellitus or ulcerative colitis, osteoporosis, transplantrejection reactions, cachexia, tumour growth or tumour metastases,sepsis, memory disorders, atherosclerosis and AIDS.

In general, the substances according to the invention are preferablyadministered in doses corresponding to the compound rolipram of between1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. Thedaily dose is preferably between about 0.02 and 10 mg/kg of body weight.However, the specific dose for each patient depends on a wide variety offactors, for example on the efficacy of the specific compound employed,on the age, body weight, general state of health, sex, on the diet, onthe time and method of administration, on the excretion rate, medicamentcombination and severity of the particular disease to which the therapyapplies. Oral administration is preferred.

EXAMPLE I Effect of the PDE IV Inhibitors of the Formula I on theProliferation of T-cells

Peripheral blood mononuclear cells (PBMC) are isolated from the blood ofhealthy donors using the Lymphoprep gradient method. 200,000 PBMC/wellare cultivated for 5 days at 37° C. and 10% CO₂ in microtitre plateswith a flat base and 96 wells in RPMI1640 culture medium with 5% ofheat-deactivated human serum (AB pool). The T-cells in the PBMCpreparation are stimulated selectively against CD3 with a monoclonalantibody. In each case, three batches of the cultures are prepared,including a control group which is not treated. The PDE IV inhibitors ofthe formula I are dissolved in DMSO to a concentration of 10⁻² M anddiluted with culture medium. DMSO is added to the control culturescorrespondingly to the inhibitor concentration. 18 hours before the endof the assay, ³H-thymidine is added to the cultures. The uptake ofradioactivity into the cells is then measured in a beta counter. Thedata from at least three independent experiments are calculated aspercentage inhibition of the control (mean±standard deviation) withoutinhibitor. The IC₅₀ value is determined from these data.

Results:

The PDE IV inhibitors of the formula I cause a significant reduction inT-cell proliferation.

EXAMPLE II Effect of the PDE IV Inhibitors of the Formula I on CytokineProduction in Human Peripheral Blood Monocytic Cells

Peripheral blood mononuclear cells (PBMC) are isolated from the blood ofhealthy donors using the Lymphoprep gradient method. 200,000 PBMC/wellare cultivated at 37° C. and 10% CO₂ in microtitre plates with a flatbase and 96 wells in RPMI1640 culture medium with 5% of heat-deactivatedhuman serum (AB pool). In each case, three batches of the cultures areprepared, including a control group. 10⁻² M solutions of the PDE IVinhibitors of the formula I in DMSO are prepared and are then dilutedwith culture medium. DMSO concentrations are added to the controlcultures correspondingly to the inhibitor concentration. The relevantcytokine is stimulated.

The culture supernatants from three independent experiments are pooled,and the cytokine activity in the supernatant is measured using acommercially available ELISA test kit. The data are calculated aspercentage inhibition/stimulation of the control group without compound,and the corresponding IC₅₀ value or EC₅₀ value is determined in the caseof stimulation.

Result

The PDE IV inhibitors of the formula I cause significantly reducedliberation of IL-2, IFN-γ, TNF-α and IL-12.

EXAMPLE III Effect of the PDE IV Inhibitors of the Formula I onExperimental Myocardial Infarction in Rats

In rats, compound 5 causes a significant, dose-dependent reduction inthe infarction size of up to 38% on intraperitoneal administration of 1,3 or 10 mg/kg 1 hour before reversible closure of the left coronaryartery. In agreement with this protection, a reduction, measured bymeans of ELISA, in the TNF-alpha concentration in the plasma isobserved.

EXAMPLE IV Effect of the PDE IV Inhibitors of the Formula I onExperimental Myocardial Infarction in Rabbits

In anaesthetised rabbits in which the coronary artery (side arm of theRamus circumflexus of the left coronary artery) is closed for 30 minutesand subsequently re-perfused for 120 minutes, PDE IV inhibition has acardioprotective action. Compared with placebo, PDE IV inhibitors of theformula I administered before the coronary closure reduced theinfarction size. The endangered regions were comparable in the verum andplacebo groups. The cardioprotective action can be ascribed tounfavourable haemodynamic effects since the heart rate and mean aortalpressure remain constant during performance of the experiment.

Above and below, all temperatures are given in ° C. In the followingexamples, “conventional work-up” means that water is added if necessary,the pH is adjusted, if necessary, to values of between 2 and 10,depending on the constitution of the end product, the mixture isextracted with ethyl acetate or dichloromethane, the phases areseparated, the organic phase is dried over sodium sulfate andevaporated, and the product is purified by chromatography on silica geland/or by crystallisation. The terms ortho (o), meta (m) and para (p)relate to the —CH₂S— or —CHN— group located on the rings.

EXAMPLE 1

0.272 g of 4-amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-one (which canbe prepared by the method of A. Dornow, H. Menzel, P. Marx, Chem. Ber.97, 2173 (1964)) was suspended in 0.86 ml of a 2N solution of sodiumhydroxide in water. A solution of 0.218 g of benzyl chloride in ethanolwas subsequently added dropwise, and the mixture was heated at 80° C.for 30 minutes. The resultant precipitate was filtered off with suction,giving 4-amino-3-benzylsulfanyl-6-methyl-4H-1,2,4-triazin-5-one.

The following compounds of the formula IIIa are obtained analogouslyusing the corresponding precursors:

IIIa

R³ R⁴ R⁵ (2) o-F H CH₃ (3) m-F H CH₃ (4) p-F H CH₃ (5) o-Cl H CH₃ (6)m-Cl H CH₃ (7) p-Cl H CH₃ (8) o-Cl o-Cl CH₃ (9) m-Cl o-Cl CH₃ (10) p-Clo-Cl CH₃ (11) m-Cl m-Cl CH₃ (12) p-Cl m-Cl CH₃ (13) o-Cl o-F CH₃ (14)m-Cl o-F CH₃ (15) p-Cl o-F CH₃ (16) o-Cl m-F CH₃ (17) m-Cl m-F CH₃ (18)p-Cl m-F CH₃ (19) o-Cl p-F CH₃ (20) m-Cl p-F CH₃ (21) o-F o-F CH₃ (22)m-F o-F CH₃ (23) p-F o-F CH₃ (24) m-F m-F CH₃ (25) p-F m-F CH₃ (26)o-OCH₃ H CH₃ (27) m-OCH₃ H CH₃ (28) p-OCH₃ H CH₃ (29) o-OCH₃ o-Cl CH₃(30) m-OCH₃ o-Cl CH₃ (31) p-OCH₃ o-Cl CH₃ (32) m-OCH₃ m-Cl CH₃ (33)p-OCH₃ m-Cl CH₃ (34) o-OCH₃ o-F CH₃ (35) m-OCH₃ o-F CH₃ (36) p-OCH₃ o-FCH₃ (37) o-OCH₃ m-F CH₃ (38) m-OCH₃ m-F CH₃ (39) p-OCH₃ m-F CH₃ (40)o-OCH₃ p-F CH₃ (41) m-OCH₃ p-F CH₃ (42) o-OCH₃ o-OCH₃ CH₃ (43) m-OCH₃o-OCH₃ CH₃ (44) p-OCH₃ o-OCH₃ CH₃ (45) m-OCH₃ m-OCH₃ CH₃ (46) p-OCH₃m-OCH₃ CH₃ (47) o-OH H CH₃ (48) m-OH H CH₃ (49) p-OH H CH₃ (50) o-OHo-Cl CH₃ (51) m-OH o-Cl CH₃ (52) p-OH o-Cl CH₃ (53) m-OH m-Cl CH₃ (54)p-OH m-Cl CH₃ (55) o-OH o-F CH₃ (56) m-OH o-F CH₃ (57) p-OH o-F CH₃ (58)o-OH m-F CH₃ (59) m-OH m-F CH₃ (60) p-OH m-F CH₃ (61) o-OH p-F CH₃ (62)m-OH p-F CH₃ (63) o-OH o-OH CH₃ (64) m-OH o-OH CH₃ (65) p-OH o-OH CH₃(66) m-OH m-OH CH₃ (67) p-OH m-OH CH₃ (68) o-CH₃ H CH₃ (69) m-CH₃ H CH₃(70) p-CH₃ H CH₃ (71) o-CH₃ o-Cl CH₃ (72) m-CH₃ o-Cl CH₃ (73) p-CH₃ o-ClCH₃ (74) m-CH₃ m-Cl CH₃ (75) p-CH₃ m-Cl CH₃ (76) o-CH₃ o-F CH₃ (77)m-CH₃ o-F CH₃ (78) p-CH₃ o-F CH₃ (79) o-CH₃ m-F CH₃ (80) m-CH₃ m-F CH₃(81) p-CH₃ m-F CH₃ (82) o-CH₃ p-F CH₃ (83) m-CH₃ p-F CH₃ (84) o-CH₃o-CH₃ CH₃ (85) m-CH₃ o-CH₃ CH₃ (86) p-CH₃ o-CH₃ CH₃ (87) m-CH₃ m-CH₃ CH₃(88) p-CH₃ m-CH₃ CH₃ (89) o-F H C₂H₅ (90) m-F H C₂H₅ (91) p-F H C₂H₅(92) o-Cl H C₂H₅ (93) m-Cl H C₂H₅ (94) p-Cl H C₂H₅ (95) o-Cl o-Cl C₂H₅(96) m-Cl o-Cl C₂H₅ (97) p-Cl o-Cl C₂H₅ (98) m-Cl m-Cl C₂H₅ (99) p-Clm-Cl C₂H₅ (100) o-Cl o-F C₂H₅ (101) m-Cl o-F C₂H₅ (102) p-Cl o-F C₂H₅(103) o-Cl m-F C₂H₅ (104) m-Cl m-F C₂H₅ (105) p-Cl m-F C₂H₅ (106) o-Clp-F C₂H₅ (107) m-Cl p-F C₂H₅ (108) o-F o-F C₂H₅ (109) m-F o-F C₂H₅ (110)p-F o-F C₂H₅ (111) m-F m-F C₂H₅ (112) p-F m-F C₂H₅ (113) o-OCH₃ H C₂H₅(114) m-OCH₃ H C₂H₅ (115) p-OCH₃ H C₂H₅ (116) o-OCH₃ o-Cl C₂H₅ (117)m-OCH₃ o-Cl C₂H₅ (118) p-OCH₃ o-Cl C₂H₅ (119) m-OCH₃ m-Cl C₂H₅ (120)p-OCH₃ m-Cl C₂H₅ (121) o-OCH₃ o-F C₂H₅ (122) m-OCH₃ o-F C₂H₅ (123)p-OCH₃ o-F C₂H₅ (124) o-OCH₃ m-F C₂H₅ (125) m-OCH₃ m-F C₂H₅ (126) p-OCH₃m-F C₂H₅ (127) o-OCH₃ p-F C₂H₅ (128) m-OCH₃ p-F C₂H₅ (129) o-OCH₃ o-OCH₃C₂H₅ (130) m-OCH₃ o-OCH₃ C₂H₅ (131) p-OCH₃ o-OCH₃ C₂H₅ (132) m-OCH₃m-OCH₃ C₂H₅ (133) p-OCH₃ m-OCH₃ C₂H₅ (134) o-OH H C₂H₅ (135) m-OH H C₂H₅(136) p-OH H C₂H₅ (137) o-OH o-Cl C₂H₅ (138) m-OH o-Cl C₂H₅ (139) p-OHo-Cl C₂H₅ (140) m-OH m-Cl C₂H₅ (141) p-OH m-Cl C₂H₅ (142) o-OH o-F C₂H₅(143) m-OH o-F C₂H₅ (144) p-OH o-F C₂H₅ (145) o-OH m-F C₂H₅ (146) m-OHm-F C₂H₅ (147) p-OH m-F C₂H₅ (148) o-OH p-F C₂H₅ (149) m-OH p-F C₂H₅(150) o-OH o-OH C₂H₅ (151) m-OH o-OH C₂H₅ (152) p-OH o-OH C₂H₅ (153)m-OH m-OH C₂H₅ (154) p-OH m-OH C₂H₅ (155) o-CH₃ H C₂H₅ (156) m-CH₃ HC₂H₅ (157) p-CH₃ H C₂H₅ (158) o-CH₃ o-Cl C₂H₅ (159) m-CH₃ o-Cl C₂H₅(160) p-CH₃ o-Cl C₂H₅ (161) m-CH₃ m-Cl C₂H₅ (162) p-CH₃ m-Cl C₂H₅ (163)o-CH₃ o-F C₂H₅ (164) m-CH₃ o-F C₂H₅ (165) p-CH₃ o-F C₂H₅ (166) o-CH₃ m-FC₂H₅ (167) m-CH₃ m-F C₂H₅ (168) p-CH₃ m-F C₂H₅ (169) o-CH₃ p-F C₂H₅(170) m-CH₃ p-F C₂H₅ (171) o-CH₃ o-CH₃ C₂H₅ (172) m-CH₃ o-CH₃ C₂H₅ (173)p-CH₃ o-CH₃ C₂H₅ (174) m-CH₃ m-CH₃ C₂H₅ (175) p-CH₃ m-CH₃ C₂H₅

The following compounds of the formula IIIb are obtained analogouslyusing the corresponding precursors:

IIIb

R³ R⁴ R⁵ (176) o-F H CH₃ (177) m-F H CH₃ (178) p-F H CH₃ (179) o-Cl HCH₃ (180) m-Cl H CH₃ (181) p-Cl H CH₃ (182) H H CH₃ (183) o-OCH₃ H CH₃(184) m-OCH₃ H CH₃ (185) p-OCH₃ H CH₃

The following compounds of the formula IIIc are obtained analogouslyusing the corresponding precursors:

IIIc

R³ R⁴ R⁵ (186) o-F H CH₃ (187) m-F H CH₃ (188) o-Cl H CH₃ (189) m-Cl HCH₃ (190) H H CH₃ (191) o-OCH₃ H CH₃ (192) m-OCH₃ H CH₃

EXAMPLE 193

0.054 g of 3-ethoxy-4-methoxybenzaldehyde and 0.017 ml of acetic acidwere added to a solution of 0.080 g of4-amino-3-(2-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one in 4ml of ethanol, and the mixture was stirred at 65° C. The resultantprecipitate was filtered off with suction, giving4-[(3-ethoxy-4-methoxybenzylidene)amino]-3-(2-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one.

The following compounds of the formula Ia are obtained analogously usingthe corresponding starting compounds:

Ia

R¹ R² R³ R⁴ R⁵ (194) OCH₃ m-OC₂H₅ H H CH₃ (195) OCH₃ m-OC₂H₅ o-Cl H CH₃(m.p. 157° C.) (196) OCH₃ m-OC₂H₅ m-Cl H CH₃ (197) OCH₃ m-OC₂H₅ p-Cl HCH₃ (198) OCH₃ m-OC₂H₅ o-F H CH₃ (m.p. 155° C.) (199) OCH₃ m-OC₂H₅ m-F HCH₃ (200) OCH₃ m-OC₂H₅ p-F H CH₃ (201) OCH₃ m-OC₂H₅ o-Cl o-Cl CH₃ (202)OCH₃ m-OC₂H₅ m-Cl o-Cl CH₃ (203) OCH₃ m-OC₂H₅ p-Cl o-Cl CH₃ (204) OCH₃m-OC₂H₅ m-Cl m-Cl CH₃ (205) OCH₃ m-OC₂H₅ p-Cl m-Cl CH₃ (206) OCH₃m-OC₂H₅ o-Cl o-F CH₃ (m.p. 234° C.) (207) OCH₃ m-OC₂H₅ m-Cl o-F CH₃(208) OCH₃ m-OC₂H₅ p-Cl o-F CH₃ (209) OCH₃ m-OC₂H₅ o-Cl m-F CH₃ (210)OCH₃ m-OC₂H₅ m-Cl m-F CH₃ (211) OCH₃ m-OC₂H₅ p-Cl m-F CH₃ (212) OCH₃m-OC₂H₅ o-CI p-F CH₃ (213) OCH₃ m-OC₂H₅ m-Cl p-F CH₃ (214) OCH₃ m-OC₂H₅o-F o-F CH₃ (215) OCH₃ m-OC₂H₅ m-F o-F CH₃ (216) OCH₃ m-OC₂H₅ p-F o-FCH₃ (217) OCH₃ m-OC₂H₅ m-F m-F CH₃ (218) OCH₃ m-OC₂H₅ p-F m-F CH₃ (219)OCH₃ m-OC₂H₅ o-OCH₃ H CH₃ (220) OCH₃ m-OC₂H₅ m-OCH₃ H CH₃ (221) OCH₃m-OC₂H₅ p-OCH₃ H CH₃ (222) OCH₃ m-OC₂H₅ o-OCH₃ o-Cl CH₃ (223) OCH₃m-OC₂H₅ m-OCH₃ o-Cl CH₃ (224) OCH₃ m-OC₂H₅ p-OCH₃ o-Cl CH₃ (225) OCH₃m-OC₂H₅ m-OCH₃ m-Cl CH₃ (226) OCH₃ m-OC₂H₅ p-OCH₃ m-Cl CH₃ (227) OCH₃m-OC₂H₅ o-OCH₃ o-F CH₃ (228) OCH₃ m-OC₂H₅ m-OCH₃ o-F CH₃ (229) OOH₃m-OC₂H₅ p-OCH₃ o-F CH₃ (230) OCH₃ m-OC₂H₅ o-OCH₃ m-F CH₃ (231) OCH₃m-OC₂H₅ m-OCH₃ m-F CH₃ (232) OCH₃ m-OC₂H₅ p-OCH₃ m-F CH₃ (233) OCH₃m-OC₂H₅ o-OCH₃ p-F CH₃ (234) OOH₃ m-OC₂H₅ m-OCH₃ p-F CH₃ (235) OCH₃m-OC₂H₅ o-OCH₃ o-OCH₃ CH₃ (236) OCH₃ m-OC₂H₅ m-OCH₃ o-OCH₃ CH₃ (237)OCH₃ m-OC₂H₅ p-OCH₃ o-OCH₃ CH₃ (238) OCH₃ m-OC₂H₅ m-OCH₃ m-OCH₃ CH₃(239) OCH₃ m-OC₂H₅ p-OCH₃ m-OCH₃ CH₃ (240) OCH₃ m-OC₂H₅ o-OH H CH₃ (241)OOH₃ m-OC₂H₅ m-OH H CH₃ (242) OCH₃ m-OC₂H₅ p-OH H CH₃ (243) OCH₃ m-OC₂H₅o-OH o-Cl CH₃ (244) OCH₃ m-OC₂H₅ m-OH o-Cl CH₃ (245) OCH₃ m-OC₂H₅ p-OHo-Cl CH₃ (246) OCH₃ m-OC₂H₅ m-OH m-Cl CH₃ (247) OCH₃ m-OC₂H₅ p-OH m-ClCH₃ (248) OCH₃ m-OC₂H₅ o-OH o-F CH₃ (249) OCH₃ m-OC₂H₅ m-OH o-F CH₃(250) OCH₃ m-OC₂H₅ p-OH o-F CH₃ (251) OCH₃ m-OC₂H₅ o-OH m-F CH₃ (252)OCH₃ m-OC₂H₅ m-OH m-F CH₃ (253) OCH₃ m-OC₂H₅ p-OH m-F CH₃ (254) OCH₃m-OC₂H₅ o-OH p-F CH₃ (255) OCH₃ m-OC₂H₅ m-OH p-F CH₃ (256) OCH₃ m-OC₂H₅o-OH o-OH CH₃ (257) OCH₃ m-OC₂H₅ m-OH o-OH CH₃ (258) OCH₃ m-OC₂H₅ p-OHo-OH CH₃ (259) OCH₃ m-OC₂H₅ m-OH m-OH CH₃ (260) OCH₃ m-OC₂H₅ p-OH m-OHCH₃ (261) OCH₃ m-OC₂H₅ o-CH₃ H CH₃ (262) OCH₃ m-OC₂H₅ m-CH₃ H CH₃ (263)OCH₃ m-OC₂H₅ p-CH₃ H CH₃ (264) OCH₃ m-OC₂H₅ o-CH₃ o-Cl CH₃ (265) OCH₃m-OC₂H₅ m-CH₃ o-Cl CH₃ (266) OCH₃ m-OC₂H₅ p-CH₃ o-Cl CH₃ (267) OCH₃m-OC₂H₅ m-CH₃ m-Cl CH₃ (268) OCH₃ m-OC₂H₅ p-CH₃ m-Cl CH₃ (269) OCH₃m-OC₂H₅ o-CH₃ o-F CH₃ (270) OCH₃ m-OC₂H₅ m-CH₃ o-F CH₃ (271) OCH₃m-OC₂H₅ p-CH₃ o-F CH₃ (272) OCH₃ m-OC₂H₅ o-CH₃ m-F CH₃ (273) OCH₃m-OC₂H₅ m-CH₃ m-F CH₃ (274) OCH₃ m-OC₂H₅ p-CH₃ m-F CH₃ (275) OCH₃m-OC₂H₅ o-CH₃ p-F CH₃ (276) OCH₃ m-OC₂H₅ m-CH₃ p-F CH₃ (277) OCH₃m-OC₂H₅ o-CH₃ o-CH₃ CH₃ (278) OCH₃ m-OC₂H₅ m-CH₃ o-CH₃ CH₃ (279) OCH₃m-OC₂H₅ p-CH₃ o-CH₃ CH₃ (280) OCH₃ m-OC₂H₅ m-CH₃ m-CH₃ CH₃ (281) OCH₃m-OC₂H₅ p-CH₃ m-CH₃ CH₃ (282) OCH₃ o-OC₂H₅ H H CH₃ (283) OCH₃ o-OC₂H₅o-Cl H CH₃ (284) OCH₃ o-OC₂H₅ m-Cl H CH₃ (285) OCH₃ o-OC₂H₅ p-Cl H CH₃(286) OCH₃ o-OC₂H₅ o-Cl o-Cl CH₃ (287) OCH₃ o-OC₂H₅ m-Cl o-Cl CH₃ (288)OCH₃ o-OC₂H₅ p-Cl o-Cl CH₃ (289) OCH₃ o-OC₂H₅ m-Cl m-Cl CH₃ (290) OCH₃o-OC₂H₅ p-Cl m-Cl CH₃ (291) OCH₃ o-OC₂H₅ o-Cl o-F CH₃ (292) OCH₃ o-OC₂H₅m-Cl o-F CH₃ (293) OCH₃ o-OC₂H₅ p-Cl o-F CH₃ (294) OCH₃ o-OC₂H₅ o-Cl m-FCH₃ (295) OCH₃ o-OC₂H₅ m-Cl m-F CH₃ (296) OCH₃ o-OC₂H₅ p-Cl m-F CH₃(297) OCH₃ o-OC₂H₅ o-Cl p-F CH₃ (298) OCH₃ o-OC₂H₅ m-Cl p-F CH₃ (299)OCH₃ o-OC₂H₅ o-F o-F CH₃ (300) OCH₃ o-OC₂H₅ m-F o-F CH₃ (301) OCH₃o-OC₂H₅ p-F o-F CH₃ (302) OCH₃ o-OC₂H₅ m-F m-F CH₃ (303) OCH₃ o-OC₂H₅p-F m-F CH₃ (304) OCH₃ o-OC₂H₅ o-OCH₃ H CH₃ (305) OCH₃ o-OC₂H₅ m-OCH₃ HCH₃ (306) OCH₃ o-OC₂H₅ p-OCH₃ H CH₃ (307) OCH₃ o-OC₂H₅ o-OCH₃ o-Cl CH₃(308) OCH₃ o-OC₂H₅ m-OCH₃ o-Cl CH₃ (309) OCH₃ o-OC₂H₅ p-OCH₃ o-Cl CH₃(310) OCH₃ o-OC₂H₅ m-OCH₃ m-Cl CH₃ (311) OCH₃ o-OC₂H₅ p-OCH₃ m-Cl CH₃(312) OCH₃ o-OC₂H₅ o-OCH₃ o-F CH₃ (313) OCH₃ o-OC₂H₅ m-OCH₃ o-F CH₃(314) OCH₃ o-OC₂H₅ p-OCH₃ o-F CH₃ (315) OCH₃ o-OC₂H₅ o-OCH₃ m-F CH₃(316) OCH₃ o-OC₂H₅ m-OCH₃ m-F CH₃ (317) OCH₃ o-OC₂H₅ p-OCH₃ m-F CH₃(318) OCH₃ o-OC₂H₅ o-OCH₃ p-F CH₃ (319) OCH₃ o-OC₂H₅ m-OCH₃ p-F CH₃(320) OCH₃ o-OC₂H₅ o-OCH₃ o-OCH₃ CH₃ (321) OOH₃ o-OC₂H₅ m-OCH₃ o-OCH₃CH₃ (322) OCH₃ o-OC₂H₅ p-OCH₃ o-OCH₃ CH₃ (323) OCH₃ o-OC₂H₅ m-OCH₃m-OCH₃ CH₃ (324) OCH₃ o-OC₂H₅ p-OCH₃ m-OCH₃ CH₃ (325) OCH₃ o-OC₂H₅ o-OHH CH₃ (326) OCH₃ o-OC₂H₅ m-OH H CH₃ (327) OCH₃ a-OC₂H₅ p-OH H CH₃ (328)OCH₃ o-OC₂H₅ o-OH o-Cl CH₃ (329) OCH₃ o-OC₂H₅ m-OH o-Cl CH₃ (330) OCH₃o-OC₂H₅ p-OH o-Cl CH₃ (331) OCH₃ o-OC₂H₅ m-OH m-Cl CH₃ (332) OCH₃o-OC₂H₅ p-OH m-Cl CH₃ (333) OCH₃ o-OC₂H₅ o-OH o-F CH₃ (334) OCH₃ o-OC₂H₅m-OH o-F CH₃ (335) OCH₃ o-OC₂H₅ p-OH o-F CH₃ (336) OCH₃ o-OC₂H₅ o-OH m-FCH₃ (337) OCH₃ o-OC₂H₅ m-OH m-F CH₃ (338) OCH₃ o-OC₂H₅ p-OH m-F CH₃(339) OCH₃ o-OC₂H₅ o-OH p-F CH₃ (340) OCH₃ o-OC₂H₅ m-OH p-F CH₃ (341)OCH₃ o-OC₂H₅ o-OH o-OH CH₃ (342) OCH₃ o-OC₂H₅ m-OH o-OH CH₃ (343) OCH₃o-OC₂H₅ p-OH o-OH CH₃ (344) OCH₃ o-OC₂H₅ m-OH m-OH CH₃ (345) OCH₃o-OC₂H₅ p-OH m-OH CH₃ (346) OCH₃ o-OC₂H₅ o-CH₃ H CH₃ (347) OCH₃ o-OC₂H₅m-CH₃ H CH₃ (348) OCH₃ o-OC₂H₅ p-CH₃ H CH₃ (349) OCH₃ o-OC₂H₅ o-CH₃ o-ClCH₃ (350) OCH₃ o-OC₂H₅ m-CH₃ o-Cl CH₃ (351) OCH₃ o-OC₂H₅ p-CH₃ o-Cl CH₃(352) OCH₃ o-OC₂H₅ m-CH₃ m-Cl CH₃ (353) OCH₃ o-OC₂H₅ p-CH₃ m-Cl CH₃(354) OCH₃ o-OC₂H₅ o-CH₃ o-F CH₃ (355) OCH₃ o-OC₂H₅ m-CH₃ o-F CH₃ (356)OCH₃ o-OC₂H₅ p-CH₃ o-F CH₃ (357) OCH₃ o-OC₂H₅ o-CH₃ m-F CH₃ (358) OCH₃o-OC₂H₅ m-CH₃ m-F CH₃ (359) OCH₃ o-OC₂H₅ p-CH₃ m-F CH₃ (360) OCH₃o-OC₂H₅ o-CH₃ p-F CH₃ (361) OCH₃ o-OC₂H₅ m-CH₃ p-F CH₃ (362) OCH₃o-OC₂H₅ o-CH₃ o-CH₃ CH₃ (363) OCH₃ o-OC₂H₅ m-CH₃ o-CH₃ CH₃ (364) OCH3o-OC₂H₅ p-CH₃ o-CH₃ CH₃ (365) OCH3 o-OC₂H₅ m-CH₃ m-CH₃ CH₃ (366) OCH3o-OC₂H₅ p-CH₃ m-CH₃ CH₃ (367) OCH₃ m-OCH₃ H H CH₃ (368) OCH₃ m-OCH₃ o-ClH CH₃ (369) OCH₃ m-OCH₃ m-Cl H CH₃ (370) OCH₃ m-OCH₃ p-Cl H CH₃ (371)OCH₃ m-OCH₃ o-Cl o-Cl CH₃ (372) OCH₃ m-OCH₃ m-Cl o-Cl CH₃ (373) OCH₃m-OCH₃ p-Cl o-Cl CH₃ (374) OCH₃ m-OCH₃ m-Cl m-Cl CH₃ (375) OCH₃ m-OCH₃p-Cl m-Cl CH₃ (376) OCH₃ m-OCH₃ o-Cl o-F CH₃ (377) OCH₃ m-OCH₃ m-Cl o-FCH₃ (378) OCH₃ m-OCH₃ p-Cl o-F CH₃ (379) OCH₃ m-OCH₃ o-Cl m-F CH₃ (380)OCH₃ m-OCH₃ m-Cl m-F CH₃ (381) OCH₃ m-OCH₃ p-Cl m-F CH₃ (382) OCH₃m-OCH₃ o-Cl p-F CH₃ (383) OCH₃ m-OCH₃ m-Cl p-F CH₃ (384) OCH₃ m-OCH₃ o-Fo-F CH₃ (385) OCH₃ m-OCH₃ m-F o-F CH₃ (386) OCH₃ m-OCH₃ p-F o-F CH₃(387) OCH₃ m-OCH₃ m-F m-F CH₃ (388) OCH₃ m-OCH₃ p-F m-F CH₃ (389) OCH₃m-OCH₃ o-OCH₃ H CH₃ (390) OCH₃ m-OCH₃ m-OCH₃ H CH₃ (391) OCH₃ m-OCH₃p-OCH₃ H CH₃ (392) OCH₃ m-OCH₃ o-OCH₃ o-Cl CH₃ (393) OCH₃ m-OCH₃ m-OCH₃o-Cl CH₃ (394) OCH₃ m-OCH₃ p-OCH₃ o-Cl CH₃ (395) OCH₃ m-OCH₃ m-OCH₃ m-ClCH₃ (396) OCH₃ m-OCH₃ p-OCH₃ m-Cl CH₃ (397) OCH₃ m-OCH₃ o-OCH₃ o-F CH₃(398) OCH₃ m-OCH₃ m-OCH₃ o-F CH₃ (399) OCH₃ m-OCH₃ p-OCH₃ o-F CH₃ (400)OCH₃ m-OCH₃ o-OCH₃ m-F CH₃ (401) OCH₃ m-OCH₃ m-OCH₃ m-F CH₃ (402) OCH₃m-OCH₃ p-OCH₃ m-F CH₃ (403) OCH₃ m-OCH₃ o-OCH₃ p-F CH₃ (404) OCH₃ m-OCH₃m-OCH₃ p-F CH₃ (405) OCH₃ m-OCH₃ o-OCH₃ o-OCH₃ CH₃ (406) OCH₃ m-OCH₃m-OCH₃ o-OCH₃ CH₃ (407) OCH₃ m-OCH₃ p-OCH₃ o-OCH₃ CH₃ (408) OCH₃ m-OCH₃m-OCH₃ m-OCH₃ CH₃ (409) OCH₃ m-OCH₃ p-OCH₃ m-OCH₃ CH₃ (410) OCH₃ m-OCH₃o-OH H CH₃ (411) OCH₃ m-OCH₃ m-OH H CH₃ (412) OCH₃ m-OCH₃ p-OH H CH₃(413) OCH₃ m-OCH₃ o-OH o-Cl CH₃ (414) OCH₃ m-OCH₃ m-OH o-Cl CH₃ (415)OCH₃ m-OCH₃ p-OH o-Cl CH₃ (416) OCH₃ m-OCH₃ m-OH m-Cl CH₃ (417) OCH₃m-OCH₃ p-OH m-Cl CH₃ (418) OCH₃ m-OCH₃ o-OH o-F CH₃ (419) OCH₃ m-OCH₃m-OH o-F CH₃ (420) OCH₃ m-OCH₃ p-OH o-F CH₃ (421) OCH₃ m-OCH₃ o-OH m-FCH₃ (422) OCH₃ m-OCH₃ m-OH m-F CH₃ (423) OCH₃ m-OCH₃ p-OH m-F CH₃ (424)OCH₃ m-OCH₃ o-OH p-F CH₃ (425) OCH₃ m-OCH₃ m-OH p-F CH₃ (426) OCH₃m-OCH₃ o-OH o-OH CH₃ (427) OCH₃ m-OCH₃ m-OH o-OH CH₃ (428) OCH₃ m-OCH₃p-OH o-OH CH₃ (429) OCH₃ m-OCH₃ m-OH m-OH CH₃ (430) OCH₃ m-OCH₃ p-OHm-OH CH₃ (431) OCH₃ m-OCH₃ o-CH₃ H CH₃ (432) OCH₃ m-OCH₃ m-CH₃ H CH₃(433) OCH₃ m-OCH₃ p-CH₃ H CH₃ (434) OCH₃ m-OCH₃ o-CH₃ o-Cl CH₃ (435)OCH₃ m-OCH₃ m-CH₃ o-Cl CH₃ (436) OCH₃ m-OCH₃ p-CH₃ o-Cl CH₃ (437) OCH₃m-OCH₃ m-CH₃ m-Cl CH₃ (438) OCH₃ m-OCH₃ p-CH₃ m-Cl CH₃ (439) OCH₃ m-OCH₃o-CH₃ o-F CH₃ (440) OCH₃ m-OCH₃ m-CH₃ o-F CH₃ (441) OCH₃ m-OCH₃ p-CH₃o-F CH₃ (442) OCH₃ m-OCH₃ o-CH₃ m-F CH₃ (443) OCH₃ m-OCH₃ m-CH₃ m-F CH₃(444) OCH₃ m-OCH₃ p-CH₃ m-F CH₃ (445) OCH₃ m-OCH₃ o-CH₃ p-F CH₃ (446)OCH₃ m-OCH₃ m-CH₃ p-F CH₃ (447) OCH₃ m-OCH₃ o-CH₃ o-CH₃ CH₃ (448) OCH₃m-OCH₃ m-CH₃ o-CH₃ CH₃ (449) OCH₃ m-OCH₃ p-CH₃ o-CH₃ CH₃ (450) OCH₃m-OCH₃ m-CH₃ m-CH₃ CH₃ (451) OCH₃ m-OCH₃ p-CH₃ m-CH₃ CH₃ (452) OCH₃ H HH CH₃ (453) OCH₃ H o-Cl H CH₃ (454) OCH₃ H m-Cl H CH₃ (455) OCH₃ H p-ClH CH₃ (456) OCH₃ H o-Cl o-Cl CH₃ (457) OCH₃ H m-Cl o-Cl CH₃ (458) OCH₃ Hp-Cl o-Cl CH₃ (459) OCH₃ H m-Cl m-Cl CH₃ (460) OCH₃ H p-Cl m-Cl CH₃(461) OCH₃ H o-Cl o-F CH₃ (462) OCH₃ H m-Cl o-F CH₃ (463) OCH₃ H p-Clo-F CH₃ (464) OCH₃ H o-Cl m-F CH₃ (465) OCH₃ H m-Cl m-F CH₃ (466) OCH₃ Hp-Cl m-F CH₃ (467) OCH₃ H o-Cl p-F CH₃ (468) OCH₃ H m-Cl p-F CH₃ (469)OCH₃ H o-F o-F CH₃ (470) OCH₃ H m-F o-F CH₃ (471) OCH₃ H p-F o-F CH₃(472) OCH₃ H m-F m-F CH₃ (473) OCH₃ H p-F m-F CH₃ (474) OCH₃ H o-OCH₃ HCH₃ (475) OCH₃ H m-OCH₃ H CH₃ (476) OCH₃ H p-OCH₃ H CH₃ (477) OCH₃ Ho-OCH₃ o-Cl CH₃ (478) OCH₃ H m-OCH₃ o-Cl CH₃ (479) OCH₃ H p-OCH₃ o-ClCH₃ (480) OCH₃ H m-OCH₃ m-Cl CH₃ (481) OCH₃ H p-OCH₃ m-Cl CH₃ (482) OCH₃H o-OCH₃ o-F CH₃ (483) OCH₃ H m-OCH₃ o-F CH₃ (484) OCH₃ H p-OCH₃ o-F CH₃(485) OCH₃ H o-OCH₃ m-F CH₃ (486) OCH₃ H m-OCH₃ m-F CH₃ (487) OCH₃ Hp-OCH₃ m-F CH₃ (488) OCH₃ H o-OCH₃ p-F CH₃ (489) OCH₃ H m-OCH₃ p-F CH₃(490) OCH₃ H o-OCH₃ o-OCH₃ CH₃ (491) OCH₃ H m-OCH₃ o-OCH₃ CH₃ (492) OCH₃H p-OCH₃ o-OCH₃ CH₃ (493) OCH₃ H m-OCH₃ m-OCH₃ CH₃ (494) OCH₃ H p-OCH₃m-OCH₃ CH₃ (495) OCH₃ H o-OH H CH₃ (496) OCH₃ H m-OH H CH₃ (497) OCH₃ Hp-OH H CH₃ (498) OCH₃ H o-OH o-Cl CH₃ (499) OCH₃ H m-OH o-Cl CH₃ (500)OCH₃ H p-OH o-Cl CH₃ (501) OCH₃ H m-OH m-Cl CH₃ (502) OCH₃ H p-OH m-ClCH₃ (503) OCH₃ H o-OH o-F CH₃ (504) OCH₃ H m-OH o-F CH₃ (505) OCH₃ Hp-OH o-F CH₃ (506) OCH₃ H o-OH m-F CH₃ (507) OCH₃ H m-OH m-F CH₃ (508)OCH₃ H p-OH m-F CH₃ (509) OCH₃ H o-OH p-F CH₃ (510) OCH₃ H m-OH p-F CH₃(511) OCH₃ H o-OH o-OH CH₃ (512) OCH₃ H m-OH o-OH CH₃ (513) OCH₃ H p-OHo-OH CH₃ (514) OCH₃ H m-OH m-OH CH₃ (515) OCH₃ H p-OH m-OH CH₃ (516)OCH₃ H o-CH₃ H CH₃ (517) OCH₃ H m-CH₃ H CH₃ (518) OCH₃ H p-CH₃ H CH₃(519) OCH₃ H o-CH₃ o-Cl CH₃ (520) OCH₃ H m-CH₃ o-Cl CH₃ (521) OCH₃ Hp-CH₃ o-C1 CH₃ (522) OCH₃ H m-CH₃ m-Cl CH₃ (523) OCH₃ H p-CH₃ m-Cl CH₃(524) OCH₃ H o-CH₃ o-F CH₃ (525) OCH₃ H m-CH₃ o-F CH₃ (526) OCH₃ H p-CH₃o-F CH₃ (527) OCH₃ H o-CH₃ m-F CH₃ (528) OCH₃ H m-CH₃ m-F CH₃ (529) OCH₃H p-CH₃ m-F CH₃ (530) OCH₃ H o-CH₃ p-F CH₃ (531) OCH₃ H m-CH₃ p-F CH₃(532) OCH₃ H o-CH₃ o-CH₃ CH₃ (533) OCH₃ H m-CH₃ o-CH₃ CH₃ (534) OCH₃ Hp-CH₃ o-CH₃ CH₃ (535) OCH₃ H m-CH₃ m-CH₃ CH₃ (536) OCH₃ H p-CH₃ m-CH₃CH₃ (537) OCH₃ o-Cl H H CH₃ (538) OCH₃ o-Cl o-Cl H CH₃ (539) OCH₃ o-Clm-Cl H CH₃ (540) OCH₃ o-Cl p-Cl H CH₃ (541) OCH₃ o-Cl o-Cl o-Cl CH₃(542) OCH₃ o-Cl m-Cl o-Cl CH₃ (543) OCH₃ o-Cl p-Cl o-Cl CH₃ (544) OCH₃o-Cl m-Cl m-Cl CH₃ (545) OCH₃ o-Cl p-Cl m-Cl CH₃ (546) OCH₃ o-Cl o-Clo-F CH₃ (547) OCH₃ o-Cl m-Cl o-F CH₃ (548) OCH₃ o-Cl p-Cl o-F CH₃ (549)OCH₃ o-Cl o-Cl m-F CH₃ (550) OCH₃ o-Cl m-Cl m-F CH₃ (551) OCH₃ o-Cl p-Clm-F CH₃ (552) OCH₃ o-Cl o-Cl p-F CH₃ (553) OCH₃ o-Cl m-Cl p-F CH₃ (554)OCH₃ o-Cl o-F o-F CH₃ (555) OCH₃ o-Cl m-F o-F CH₃ (556) OCH₃ o-Cl p-Fo-F CH₃ (557) OCH₃ o-Cl m-F m-F CH₃ (558) OCH₃ o-Cl p-F m-F CH₃ (559)OCH₃ o-Cl o-OCH₃ H CH₃ (560) OCH₃ o-Cl m-OCH₃ H CH₃ (561) OCH₃ o-Clp-OCH₃ H CH₃ (562) OCH₃ o-Cl o-OCH₃ o-Cl CH₃ (563) OCH₃ o-Cl m-OCH₃ o-ClCH₃ (564) OCH₃ o-Cl p-OCH₃ o-Cl CH₃ (565) OCH₃ o-Cl m-OCH₃ m-Cl CH₃(566) OCH₃ o-Cl p-OCH₃ m-Cl CH₃ (567) OCH₃ o-Cl o-OCH₃ o-F CH₃ (568)OCH₃ o-Cl m-OCH₃ o-F CH₃ (569) OCH₃ o-Cl p-OCH₃ o-F CH₃ (570) OCH₃ o-Clo-OCH₃ m-F CH₃ (571) OCH₃ o-Cl m-OCH₃ m-F CH₃ (572) OCH₃ o-Cl p-OCH₃ m-FCH₃ (573) OCH₃ o-Cl o-OCH₃ p-F CH₃ (574) OCH₃ o-Cl m-OCH₃ p-F CH₃ (575)OCH₃ o-Cl o-OCH₃ o-OCH₃ CH₃ (576) OCH₃ o-Cl m-OCH₃ o-OCH₃ CH₃ (577) OCH₃o-Cl p-OCH₃ o-OCH₃ CH₃ (578) OCH₃ o-Cl m-OCH₃ m-OCH₃ CH₃ (579) OCH₃ o-Clp-OCH₃ m-OCH₃ CH₃ (580) OCH₃ o-Cl o-OH H CH₃ (581) OCH₃ o-Cl m-OH H CH₃(582) OCH₃ o-Cl p-OH H CH₃ (583) OCH₃ o-Cl o-OH o-Cl CH₃ (584) OCH₃ o-Clm-OH o-Cl CH₃ (585) OCH₃ o-Cl p-OH o-Cl CH₃ (586) OCH₃ o-Cl m-OH m-ClCH₃ (587) OCH₃ o-Cl p-OH m-Cl CH₃ (588) OCH₃ o-Cl o-OH o-F CH₃ (589)OCH₃ o-Cl m-OH o-F CH₃ (590) OCH₃ o-Cl p-OH o-F CH₃ (591) OCH₃ o-Cl o-OHm-F CH₃ (592) OCH₃ o-Cl m-OH m-F CH₃ (593) OCH₃ o-Cl p-OH m-F CH₃ (594)OCH₃ o-Cl o-OH p-F CH₃ (595) OCH₃ o-Cl m-OH p-F CH₃ (596) OCH₃ o-Cl o-OHo-OH CH₃ (597) OCH₃ o-Cl m-OH o-OH CH₃ (598) OCH₃ o-Cl p-OH o-OH CH₃(599) OCH₃ o-Cl m-OH m-OH CH₃ (600) OCH₃ o-Cl p-OH m-OH CH₃ (601) OCH₃o-Cl o-CH₃ H CH₃ (602) OCH₃ o-Cl m-CH₃ H CH₃ (603) OCH₃ o-Cl p-CH₃ H CH₃(604) OCH₃ o-Cl o-CH₃ o-Cl CH₃ (605) OCH₃ o-Cl m-CH₃ o-Cl CH₃ (606) OCH₃o-Cl p-CH₃ o-Cl CH₃ (607) OCH₃ o-Cl m-CH₃ m-Cl CH₃ (608) OCH₃ o-Cl p-CH₃m-Cl CH₃ (609) OCH₃ o-Cl o-CH₃ o-F CH₃ (610) OCH₃ o-Cl m-CH₃ o-F CH₃(611) OCH₃ o-Cl p-CH₃ o-F CH₃ (612) OCH₃ o-Cl o-CH₃ m-F CH₃ (613) OCH₃o-Cl m-CH₃ m-F CH₃ (614) OCH₃ o-Cl p-CH₃ m-F CH₃ (615) OCH₃ o-Cl o-CH₃p-F CH₃ (616) OCH₃ o-Cl m-CH₃ p-F CH₃ (617) OCH₃ o-Cl o-CH₃ o-CH₃ CH₃(618) OCH₃ o-Cl m-CH₃ o-CH₃ CH₃ (619) OCH₃ o-Cl p-CH₃ o-CH₃ CH₃ (620)OCH₃ o-Cl m-CH₃ m-CH₃ CH₃ (621) OCH₃ o-Cl p-CH₃ m-CH₃ CH₃ (622) OCH₃m-OC₂H₅ H H C₂H₅ (623) OCH₃ m-OC₂H₅ o-Cl H C₂H₅ (624) OCH₃ m-OC₂H₅ m-ClH C₂H₅ (625) OCH₃ m-OC₂H₅ p-Cl H C₂H₅ (626) OCH₃ m-OC₂H₅ o-Cl o-Cl C₂H₅(627) OCH₃ m-OC₂H₅ m-Cl o-Cl C₂H₅ (628) OCH₃ m-OC₂H₅ p-Cl o-Cl C₂H₅(629) OCH₃ m-OC₂H₅ m-Cl m-Cl C₂H₅ (630) OCH₃ m-OC₂H₅ p-Cl m-Cl C₂H₅(631) OCH₃ m-OC₂H₅ o-Cl o-F C₂H₅ (632) OCH₃ m-OC₂H₅ m-Cl o-F C₂H₅ (633)OCH₃ m-OC₂H₅ p-Cl o-F C₂H₅ (634) OCH₃ m-OC₂H₅ o-Cl m-F C₂H₅ (635) OCH₃m-OC₂H₅ m-Cl m-F C₂H₅ (636) OCH₃ m-OC₂H₅ p-Cl m-F C₂H₅ (637) OCH₃m-OC₂H₅ o-Cl p-F C₂H₅ (638) OCH₃ m-OC₂H₅ m-Cl p-F C₂H₅ (639) OCH₃m-OC₂H₅ o-F o-F C₂H₅ (640) OCH₃ m-OC₂H₅ m-F o-F C₂H₅ (641) OCH₃ m-OC₂H₅p-F o-F C₂H₅ (642) OCH₃ m-OC₂H₅ m-F m-F C₂H₅ (643) OCH₃ m-OC₂H₅ p-F m-FC₂H₅ (644) OCH₃ m-OC₂H₅ o-OCH₃ H C₂H₅ (645) OCH₃ m-OC₂H₅ m-OCH₃ H C₂H₅(646) OCH₃ m-OC₂H₅ p-OCH₃ H C₂H₅ (647) OCH₃ m-OC₂H₅ o-OCH₃ o-Cl C₂H₅(648) OCH₃ m-OC₂H₅ m-OCH₃ o-Cl C₂H₅ (649) OCH₃ m-OC₂H₅ p-OCH₃ o-Cl C₂H₅(650) OCH₃ m-OC₂H₅ m-OCH₃ m-Cl C₂H₅ (651) OCH₃ m-OC₂H₅ p-OCH₃ m-Cl C₂H₅(652) OCH₃ m-OC₂H₅ o-OCH₃ o-F C₂H₅ (653) OCH₃ m-OC₂H₅ m-OCH₃ o-F C₂H₅(654) OCH₃ m-OC₂H₅ p-OCH₃ o-F C₂H₅ (655) OCH₃ m-OC₂H₅ o-OCH₃ m-F C₂H₅(656) OCH₃ m-OC₂H₅ m-OCH₃ m-F C₂H₅ (657) OCH₃ m-OC₂H₅ H H H (658) OCH₃m-OC₂H₅ o-Cl H H (659) OCH₃ m-OC₂H₅ m-Cl H H (660) OCH₃ m-OC₂H₅ p-Cl H H(661) OCH₃ m-OC₂H₅ o-Cl o-Cl H (662) OCH₃ m-OC₂H₅ m-Cl o-Cl H (663) OCH₃m-OC₂H₅ p-Cl o-Cl H (664) OCH₃ m-OC₂H₅ m-Cl m-Cl H (665) OCH₃ m-OC₂H₅p-Cl m-Cl H (666) OCH₃ m-OC₂H₅ o-Cl o-F H (667) OCH₃ m-OC₂H₅ m-Cl o-F H(668) OCH₃ m-OC₂H₅ p-Cl o-F H (669) OCH₃

H H CH₃ (670) OCH₃

o-Cl H CH₃ (671) OCH₃

m-Cl H CH₃ (672) OCH₃

p-Cl H CH₃ (673) OCH₃

o-F H CH₃ (m.p. 155° C.) (674) OCH₃

m-F H CH₃ (675) OCH₃

p-F H CH₃ (676) OCH₃

o-Cl o-Cl CH₃ (677) OCH₃

m-Cl o-Cl CH₃ (678) OCH₃

p-Cl o-Cl CH₃ (679) OCH₃

m-Cl m-Cl CH₃ (680) OCH₃

p-Cl m-Cl CH₃ (681) OCH₃

o-Cl o-F CH₃ (m.p. 180° C.) (682) OCH₃

m-Cl o-F CH₃ (683) OCH₃

p-Cl o-F CH₃ (684) OCH₃

o-Cl m-F CH₃ (685) OCH₃

m-Cl m-F CH₃ (686) OCH₃

p-Cl m-F CH₃ (687) OCH₃

o-Cl p-F CH₃ (688) OCH₃

m-Cl p-F CH₃ (689) OCH₃

o-F o-F CH₃ (690) OCH₃

m-F o-F CH₃ (691) OCH₃

p-F o-F CH₃ (692) OCH₃

m-F m-F CH₃ (693) OCH₃

p-F m-F CH₃ (694) OCH₃

o-OCH₃ H CH₃ (695) OCH₃

m-OCH₃ H CH₃ (696) OCH₃

p-OCH₃ H CH₃ (697) OCH₃

o-OCH₃ o-Cl CH₃ (698) OCH₃

m-OCH₃ o-Cl CH₃ (699) OCH₃

p-OCH₃ o-Cl CH₃ (700) OCH₃

m-OCH₃ m-Cl CH₃ (701) OCH₃

p-OCH₃ m-Cl CH₃ (702) OCH₃

o-OCH₃ o-F CH₃ (703) OCH₃

m-OCH₃ o-F CH₃ (704) OCH₃

p-OCH₃ o-F CH₃ (705) OCH₃

o-OCH₃ m-F CH₃ (706) OCH₃

m-OCH₃ m-F CH₃ (707) OCH₃

p-OCH₃ m-F CH₃ (708) OCH₃

o-OCH₃ p-F CH₃ (709) OCH₃

m-OCH₃ p-F CH₃ (710) OCH₃

o-OCH₃ o-OCH₃ CH₃ (711) OCH₃

m-OCH₃ o-OCH₃ CH₃ (712) OCH₃

p-OCH₃ o-OCH₃ CH₃ (713) OCH₃

m-OCH₃ m-OCH₃ CH₃ (714) OCH₃

p-OCH₃ m-OCH₃ CH₃ (715) OCH₃

o-OH H CH₃ (716) OCH₃

m-OH H CH₃ (717) OCH₃

p-OH H CH₃ (718) OCH₃

o-OH o-Cl CH₃ (719) OCH₃

m-OH o-Cl CH₃ (720) OCH₃

p-OH o-Cl CH₃ (721) OCH₃

m-OH m-Cl CH₃ (722) OCH₃

p-OH m-Cl CH₃ (723) OCH₃

o-OH o-F CH₃ (724) OCH₃

m-OH o-F CH₃ (725) OCH₃

p-OH o-F CH₃ (726) OCH₃

o-OH m-F CH₃ (727) OCH₃

m-OH m-F CH₃ (728) OCH₃

p-OH m-F CH₃ (729) OCH₃

o-OH p-F CH₃ (730) OCH₃

m-OH p-F CH₃ (731) OCH₃

o-OH o-OH CH₃ (732) OCH₃

m-OH o-OH CH₃ (733) OCH₃

p-OH o-OH CH₃ (734) OCH₃

m-OH m-OH CH₃ (735) OCH₃

p-OH m-OH CH₃ (736) OCH₃

o-CH₃ H CH₃ (737) OCH₃

m-CH₃ H CH₃ (738) OCH₃

p-CH₃ H CH₃ (739) OCH₃

o-CH₃ o-Cl CH₃ (740) OCH₃

m-CH₃ o-Cl CH₃ (741) OCH₃

p-CH₃ o-Cl CH₃ (742) OCH₃

m-CH₃ m-Cl CH₃ (743) OCH₃

p-CH₃ m-Cl CH₃ (744) OCH₃

o-CH₃ o-F CH₃ (745) OCH₃

m-CH₃ o-F CH₃ (746) OCH₃

p-CH₃ o-F CH₃ (747) OCH₃

o-CH₃ m-F CH₃ (748) OCH₃

m-CH₃ m-F CH₃ (749) OCH₃

p-CH₃ m-F CH₃ (750) OCH₃

o-CH₃ p-F CH₃ (751) OCH₃

m-CH₃ p-F CH₃ (752) OCH₃

o-CH₃ o-CH₃ CH₃ (753) OCH₃

m-CH₃ o-CH₃ CH₃ (754) OCH₃

p-CH₃ o-CH₃ CH₃ (755) OCH₃

m-CH₃ m-CH₃ CH₃ (756) OCH₃

p-CH₃ m-CH₃ CH₃

The following compounds of the formula Ib are obtained analogously usingthe corresponding starting compounds:

Ib

R¹ R² R³ R⁴ R⁵ (757) OCH₃ m-OC₂H₅ H H CH₃ (m.p. 220° C.) (758) OCH₃m-OC₂H₅ o-Cl H CH₃ (759) OCH₃ m-OC₂H₅ m-Cl H CH₃ (760) OCH₃ m-OC₂H₅ p-ClH CH₃ (761) OCH₃ m-OC₂H₅ o-F H CH₃ (762) OCH₃ m-OC₂H₅ m-F H CH₃ (763)OCH₃ m-OC₂H₅ p-F H CH₃ (764) OCH₃

H H CH₃ (m.p. 169° C.) (765) OCH₃

o-Cl H CH₃ (766) OCH₃

m-Cl H CH₃ (767) OCH₃

p-Cl H CH₃ (768) OCH₃

o-F H CH₃ (769) OCH₃

m-F H CH₃ (770) OCH₃

p-F H CH₃

The following compounds of the formula Ic are obtained analogously usingthe corresponding starting compounds:

Ic

R¹ R² R³ R⁴ R⁵ (771) OCH₃ m-OC₂H₅ H H CH₃ (772) OCH₃ m-OC₂H₅ o-Cl H CH₃(773) OCH₃ m-OC₂H₅ m-Cl H CH₃ (774) OCH₃ m-OC₂H₅ o-F H CH₃ (775) OCH₃m-OC₂H₅ m-F H CH₃

The examples below relate to pharmaceutical preparations:

Example A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I is meltedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced in aconventional manner into hard gelatine capsules in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

EXAMPLE I Inhalation Spray

14 g of active ingredient of the formula I are dissolved in 10 l ofisotonic NaCl solution, and the solution is transferred intocommercially available spray containers with pump mechanism. Thesolution can be sprayed into the mouth or nose. One spray shot (about0.1 ml) corresponds to a dose of about 0.14 mg.

1. A compound of formula I

wherein R¹ and R² are each, independently of one another, H, OH, OR⁶,SR⁶, SOR⁶, SO₂R⁶, Hal or together are alternatively —O—CH₂—O—, A is R³-and R⁴-substituted phenyl, 2-, 3- or 4-pyridyl, 4- or 5-pyrimidyl, 3- or4-pyridazyl or 2- or 3-pyrazinyl, R³ and R⁴ are each, independently ofone another, H, OH, OR⁶, SR⁶, SOR⁶, SO₂R⁶, R⁶, Hal or together arealternatively —O—CH₂—O—, R⁵ is H or alkyl having from 1 to 10 carbonatoms, R⁶ is alkyl having from 1 to 10 carbon atoms, which may besubstituted by from 1 to 5 F and/or Cl atoms, cycloalkyl having 3-7carbon atoms, alkylenecycloalkyl having 5-10 carbon atoms or alkenylhaving 2-8 carbon atoms, Hal is F, Cl, Br or I, and physiologicallyacceptable salts and solvates thereof.
 2. The compound of claim 1,wherein R⁵ is a methyl group.
 3. The compound of claim 1, wherein R¹ andR² are each, independently of one another, OR⁶.
 4. The compound of claim1, wherein R⁶ is an alkyl group having 1-10 carbon atoms or a cycloalkylgroup having 3-7 carbon atoms.
 5. The compound of claim 1, wherein A isphenyl, 2-,3- or 4-pyridyl or 4- or 5-pyrimidyl, and R³ and R⁴ are each,independently of one another, R⁶, H, Cl, F, CF₃ or OR⁶.
 6. The compoundof claim 1, which is: (a)4-[(3-ethoxy-4-methoxybenzylidene)amino]-3-(benzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one,(b)4-[(3-ethoxy-4-methoxybenzylidene)amino]-3-(2-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one,(c)4-[(3-ethoxy-4-methoxybenzylidene)amino]-3-(2-chloro-6-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one,(d)4-[(3-ethoxy-4-methoxybenzylidene)amino]-6-methyl-3-(pyridin-3-ylmethylsulfanyl)-4H-1,2,4-triazin-5-one,(e)4-[(3-cyclopentyloxy-4-methoxybenzylidene)amino]-3-(benzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one,(f)4-[(3-cyclopentyloxy-4-methoxybenzylidene)amino]-3-(2-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one,(g)4-[(3-cyclopentyloxy-4-methoxybenzylidene)amino]-3-(2-chloro-6-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one,or (h)4-[(3-cyclopentyloxy-4-methoxybenzylidene)amino]-6-methyl-3-(pyridin-3-ylmethylsulfanyl)-4H-1,2,4-triazin-5-one,and physiologically acceptable salts and solvates thereof.
 7. A processfor the preparation of a compound of claim 1 comprising reacting acompound of formula II

wherein R¹ and R² are as defined in claim 1, with a compound of theformula III

wherein A and R⁵ are as defined in claim 1, and optionally converting abasic compound of formula I into a salt by treatment with an acid.
 8. Amethod of inhibiting phosphodiesterase IV, comprising contacting saidphosphodiesterase with a compound of claim
 1. 9. A pharmaceuticalpreparation comprising at least one compound of claim 1 and apharmaceutically acceptable excipient or adjuvant.
 10. A process for thepreparation of a pharmaceutical preparation comprising converting atleast one compound of claim 1 into a suitable dosage form together withat least one solid, liquid or semi-liquid excipient or adjuvant.